An Open-Label, Multicenter, Phase 1/2 Study of Allogeneic Dual-target CD70/CAIX (CA9) Chimeric Antigen Receptor Natural Killer Cells in Adults With Advanced or Metastatic Clear Cell Renal Cell Carcinoma

Advanced clear cell RCC remains difficult to treat after immune checkpoint blockade and VEGF-pathway therapy. Both CD70 and CAIX are attractive RCC targets: CAIX is broadly expressed in clear cell RCC, while CD70 is frequently overexpressed and has already generated encouraging clinical cell-therapy signals in RCC [3-11]. The investigational product in this example is an allogeneic, cord blood-derived NK cell product engineered to express a dual CAR recognizing CD70 and CAIX/CA9, membrane-bound IL-15 to enhance persistence, and an inducible caspase-9 safety switch to improve controllability. The allogeneic CAR-NK strategy is intended to provide an off-the-shelf platform with lower theoretical risk of graft-versus-host disease than allogeneic T-cell products and with innate NK killing as a complementary antitumor mechanism [1, 2, 11]. The study uses a standard dose-escalation phase followed by a biomarker-guided expansion phase. All participants receive lymphodepletion with fludarabine and cyclophosphamide and then one infusion of dual-target CAR-NK cells on Day 0; an optional second infusion on Day 15 is allowed for participants without doselimiting toxicity, uncontrolled cytokine-mediated toxicity, or rapid progression.

During expansion, participants remain in a single treatment arm but are prospectively analyzed in CD70-high, CAIX-high, and dual-high subgroups. Because earlier CAIX CAR-T studies in metastatic RCC reported on-target hepatobiliary toxicity related to low-level CAIX expression in biliary epithelium, this example protocol incorporates enhanced liver screening, exclusion of significant biliary disease, staggered first-patient dosing at each dose level, frequent liver function monitoring, and an explicit early stopping rule for recurrent protocoldefined hepatobiliary toxicity [5, 6].

The translational objective is not only to identify a recommended phase 2 dose but also to learn which antigen context appears most actionable in patients. If activity clusters in CD70-high tumors with cleaner safety, later development may pivot toward a CD70-led construct. If CAIX-high tumors uniquely benefit without meaningful hepatobiliary toxicity, CAIX/CA9 may remain central. If dual-high tumors clearly outperform single-high tumors without added risk, the dual-target program should continue.